208151Orig1s000

Home , Methylatropine, Oxyphenonium bromide

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

208151Orig1s000

MEDICAL REVIEW(S) CLINICAL REVIEW of NDA 208-151

Application Type Original NDA Application Number(s) 208-151 Priority or Standard Standard Review Submit Date(s) 2/12/2016 Received Date(s) 2/12/2016

Division / Office Division of Transplant and Ophthalmology Products, Office of Antimicrobial Products

Reviewer Name(s) Wiley A. Chambers, MD Review Completion Date September 13, 2016

Established Name Atropine ophthalmic solution Therapeutic Class Anticholinergic Applicant Alcon Research, Ltd 6201 South Freeway Fort Worth, TX 76134-2099

Proposed Indication(s) Cycloplegia Pupillary dilation Amblyopia (b) (4)

Template Version: March 6, 2009

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 2 NDA 208-151

Table of Contents

1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT...... 4 1.1 Recommendation on Regulatory Action ...... 4 1.2 Risk Benefit Assessment ...... 4 1.3 Recommendations for Post marketing Risk Evaluation and Mitigation Strategies ...... 4 1.4 Recommendations for Post marketing Requirements and Commitments ...... 4 2 INTRODUCTION AND REGULATORY BACKGROUND ...... 4 2.1 Product Information ...... 4 2.2 Tables of Currently Available Treatments for Proposed Indications...... 5 2.4 Important Safety Issues with Consideration to Related Drugs ...... 5 2.5 Summary of Presubmission Regulatory Activity Related to Submission ...... 5 3 ETHICS AND GOOD CLINICAL PRACTICES...... 5 3.1 Submission Quality and Integrity ...... 5 3.2 Compliance with Good Clinical Practices ...... 6 3.3 Financial Disclosures...... 6 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES...... 7 4.1 Chemistry Manufacturing and Controls ...... 7 4.2 Clinical Microbiology ...... 8 4.3 Nonclinical Pharmacology/Toxicology ...... 8 4.4 Clinical Pharmacology ...... 9 4.4.1 Mechanism of Action ...... 9 4.4.2 Pharmacodynamics...... 9 4.4.3 Pharmacokinetics ...... 9 5 SOURCES OF CLINICAL DATA...... 10 5.1 Tables of Studies/Clinical Trials...... 10 5.2 Review Strategy and Linkage (Bridge) to Proposed Product ...... 13 5.3 Discussion of Representative Individual Studies/Clinical Trials...... 14 6 REVIEW OF EFFICACY ...... 15 6.1 Mydriasis and Cycloplegia ...... 15 6.2 Treatment of Amblyopia...... 27 6.3 (b) (4) ...... 29 7 REVIEW OF SAFETY...... 36 7.1 Methods ...... 36 7.1.1 Studies/Clinical Trials Used to Evaluate Safety ...... 36 7.1.2 Categorization of Adverse Events...... 36 7.2 Adequacy of Safety Assessments ...... 36

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 3 NDA 208-151

7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations ...... 36 7.2.2 Explorations for Dose Response...... 36 7.2.3 Special Animal and/or In Vitro Testing ...... 36 7.3 Major Safety Results...... 36 7.3.1 Deaths ...... 36 7.3.2 Nonfatal Serious Adverse Events...... 37 7.3.3 Dropouts and/or Discontinuations ...... 37 7.3.4 Significant Adverse Events...... 37 7.4 Supportive Safety Results ...... 38 7.4.1 Common Adverse Events...... 38 7.4.2 Laboratory Findings...... 38 7.4.3 Vital Signs ...... 38 7.4.4 Electrocardiograms (ECGs) ...... 38 7.4.5 Special Safety Studies/Clinical Trials...... 38 7.4.6 Immunogenicity ...... 38 7.5 Other Safety Explorations...... 38 7.6 Additional Safety Evaluations ...... 38 7.6.1 Human Carcinogenicity ...... 38 7.6.3 Pediatrics and Assessment of Effects on Growth ...... 39 7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ...... 39 7.7 Summary of Safety ...... 39 8 LABELING ...... 40

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 4 NDA 208-151

1 Recommendations/Risk Benefit Assessment 1.1 Recommendation on Regulatory Action NDA 208-151, atropine ophthalmic solution, 1%, an anticholinergic is recommended to be approved for use in creating pupillary dilation (mydriasis), cycloplegia, and for penalization of the healthy eye in the treatment of amblyopia. (b) (4)

1.2 Risk Benefit Assessment Pupillary dilation and cycloplegia impair visual function. When multiday pupillary dilation is required and/or pupillary dilation in the setting of ocular inflammation is required, the benefits outweigh the risks associated with the use of atropine. These risks are based on its known action as anticholinergic pharmacologic action in an otherwise normal individual.

When maximal cycloplegia is required in the setting of an ophthalmic examination or in the treatment ocular inflammation, the benefits of the use of atropine outweigh the known and potential risks.

The benefits outweigh the risks when atropine ophthalmic solution is used for ocular penalization as an alternative to ocular penalization by patching in the treatment of amblyopia.

1.3 Recommendations for Post marketing Risk Evaluation and Mitigation Strategies Routine monitoring is recommended.

1.4 Recommendations for Post marketing Requirements and Commitments There are no recommended post marketing requirements.

2 Introduction and Regulatory Background

2.1 Product Information Atropine ophthalmic solution has been used for pupillary dilation and cycloplegia for over 100 years.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 5 NDA 208-151

2.2 Tables of Currently Available Treatments for Proposed Indications Drug Substance Duration (normal Action Subject of an individual) approved application Phenylephrine ~ 4 hours Mydriasis Yes Tropicamide ~ 4 hours Mydriasis & Cycloplegia Yes Cyclopentolate ~ 12 hours Mydriasis & Cycloplegia Yes Scopolamine ~ 72 hours Mydriasis & Cycloplegia No Homatropine ~ 48 hours Mydriasis & Cycloplegia No Atropine ~14 days Mydriasis, Cycloplegia, Yes and in the treatment of amblyopia

2.3 Availability of Proposed Active Ingredient in the United States Atropine ophthalmic solution is currently marketed by the applicant and a number of other manufacturers without an approved new drug applications. Akorn’s atropine ophthalmic solution, 1% is the only approved atropine ophthalmic solution.

Other dosage forms of atropine are marketed in the United States. Some of these products have approved new drug applications and others do not.

2.4 Important Safety Issues with Consideration to Related Drugs Pupillary dilation and cycloplegia impair visual function. When these actions are necessary for greater than 72 hours either for diagnostic or therapeutic action, there are no pharmacologic alternatives. When maximal cycloplegia is required, there are no therapeutic alternatives.

2.5 Summary of Presubmission Regulatory Activity Related to Submission The Applicant requested a “Pre-IND” meeting with the Division of Transplant and Ophthalmology Products. The meeting took place on February 11, 2013, during which the Agency agreed that a 505(b)(2) application was an acceptable pathway for a new drug application in which the applicant did not have a right to reference studies conducted in support of the drug product.

3 Ethics and Good Clinical Practices 3.1 Submission Quality and Integrity There is no evidence that the submitted studies were not conducted in accordance with acceptable clinical ethical standards.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 6 NDA 208-151

3.2 Compliance with Good Clinical Practices The clinical studies included in this application appeared to conform to Good Clinical Practices.

3.3 Financial Disclosures The clinical studies included in this application were conducted in Europe and the US prior to any requirements for financial disclosures.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 7 NDA 208-151

4 Significant Efficacy/Safety Issues Related to Other Review Disciplines

4.1 Chemistry Manufacturing and Controls

Formulation: Ingredient Function W/V Atropine sulfate monohydrate Active 1.0* Hypromellose (b) (4) Benzalkonium Chloride Preservative 0.01 Boric Acid (b) (4) (b) Sodium hydroxide pH adjuster To adjust pH (4) (b) Hydrochloric acid pH adjuster To adjust pH (4) Purified Water (b) (4) *Quantity equivalent to 8.3 mg/mL of Atropine.

Drug Product Specifications Parameter Target Range Atropine sulfate monohydrate (b) (4) mg/mL (b) (4) % (b) (b) (4) Benzalkonium chloride (4) mg/mL % (b) (4) (b) NMT(4) % (b) (4) (b) Impurity @ RRT NMT (4) % (b) Any Single Unspecified Impurity* NMT (4) % (b) Total Impurities NMT (4) % pH 3.5 to 6.0 Viscosity (b) (4) cps Osmolality 260 to 330 mOsm/Kg Product Appearance Colorless to (b) (4) NMT Ph Eur II Sterility Sterile Sterile Particulate Matter NMT (b) (4) 10µm NMT (b) (4) 10µm (b) (b) NMT (4) 25µm NMT (4) 25µm (b) (b) NMT (4) 50µm NMT (4) 50µm * Report any impurity ≥(b) (4) % of active except drug substance synthetic/process impurities

Reviewer's Comments: Acceptable.

Reference ID: 3985196

Clinical Review Wiley A. Chambers, MD 9 NDA 208-151

4.4 Clinical Pharmacology 4.4.1 Mechanism of Action The drug product causes local and systemic anticholinergic effects.

4.4.2 Pharmacodynamics Lahdes K et al. Systemic absorption of topically applied ocular atropine. Clin Pharmacol Ther 1988; 44:310-4.

Atropine plasma levels, blood pressure, heart rate, and salivary secretion were monitored after ocular application. Eight patients received 40 µL, 1% atropine in the lower cul-de-sac of one eye in connection with ocular surgery. Atropine plasma levels were determined for 90 minutes by radioreceptor assay. A peak plasma atropine concentration of 860 ± 402 pg/mL was reached within 8 minutes in all patients. The ocular absorption of atropine was at least as rapid as that reported for intramuscular administration. Ocular atropine did not affect patient’s blood pressure or heart rate when compared with those of the placebo group. Thirty minutes after administration of atropine eye drops, the salivary secretion in the experimental group was reduced, but was statistically insignificant from the placebo group.

4.4.3 Pharmacokinetics Kaila T et al. Systemic bioavailability of ocularly applied 1% atropine eye drops. Acta Ophthalmol. Scand. 1999: 77: 193–196

Randomized, crossover study. 0.3 mg atropine either intravenously or ocularly to six healthy volunteers. The plasma concentrations of the biologically active atropine enantiomer, 1-hyoscyamine, were determined using a muscarinic cholinoceptor binding assay.

The mean area under the curve from zero to infinitum (AUC0–) for 1-hyoscyamine was 1.862±0.580 µg/L∙hr after intravenous, and 1.092±0.381 µg/L∙hr after ocular administration (mean ± sd, n=6), respectively. The mean bioavailability was 63.5±28.6% (min 19%, max 95%). Large inter-individual differences characterized the absorption and elimination phases of 1-hyoscyamine kinetics. The terminal half-life (t½ß) of 1-hyoscyamine in plasma was not affected by the route of drug administration.

Age affects the elimination of atropine from the systemic circulation. In young children, less than 2 years of age, a larger volume of distribution is responsible for prolonged elimination and in the elderly, greater than 65 years of age, clearance is decreased. Age has no effect on the serum protein binding of atropine. [Virtanen et al. Acta Anaesth. Scand. 1982;26:297-300.]

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 10 NDA 208-151

5 Sources of Clinical Data

5.1 Tables of Studies/Clinical Trials # First Author Title Journal Year Source of Drug Product 1 Barbee RF A comparative study of mydriatic and cycloplegic agents Am J Ophthalmol ;44(5 Pt 1957 Not identified 1):617-22 2 Caruba Preolperative mydriasis obtained by ophthalmic insert J Fr Ophthalmol; 29(7): 789- 2006 versus eye drops 795. 3 Celebi The comparison of cyclopentolate and atropine in Acta Ophthalmologica 1999 Not identified patients with refractive accommodative esotropia by Scandinavica 77:426-429 means of retinoscopy, autorefractometry and biometric lens thickness (b) (4)

6 Ebri A Cost-Effectiveness of Cycloplegia Agents: Results of a Invest Ophthalmol Vis Sci 2007 Not identified Randomized Controlled Trial in Nigerian Children 48(3):1025-1031 (b) (4)

8 Fan DSP Comparative study on the Safety and Efficacy of Clinical and Experimental 2004 CibaVision different cycloplegics agents in children with darkly Ophthalmology 32:462-467 pigmented irides 9 Foley-Nolan Atropine penalisation versus occlusion as the Br J Ophthalmology 81:54- 1997 Not identified primary treatment for amblyopia 57. 10 Kaila T Systemic bioavailability of ocular applied 1% atropine Acta Ophthalmol Scand 1999 Star Pharmaceuticals eyedrops 77:193-196 Tampere, Finland (b) (4)

12 Liu Evaluation of Cycloplegic Effect of Cyclopentolate and Chin J Exp Ophthalmol 2012 Shenyang Xingqi Atropine 30(4): 353-356 Pharmaceutical Co., Ltd. 13 McCormick Pupil dilation using a pledget sponge: a randomized Clinical and Experimental 2006 Not identified controlled trial Ophthalmology 34:545-549. 14 Miranda Residual Accommodation Arch Ophthal 87:515-517 1972 15 Pediatric Eye Patching vs Atropine to treat Amblyopia in Children Arch Ophthalmol 2008 Not identified Disease Aged 7 to 12 years: A randomized trial 126(12):1634-1642 Investigator Group 16 Repka MX Treatment of severe amblyopia with weekend atropine: J AAPOS 13:258-263 2009 Not identified Results from 2 randomized clinical trials 17 Salazar M Iris Pigmentation and Atropine Mydriasis J Pharm Exp Therapeutics 1975 Supported in part by 197(1):79-88 Alcon (b) (4)

19 Tejedor Comparative Efficacy of Penalization Methods in Am J Ophthalmol 145:562- 2008 Colircusi Atropina Moderate to Mild Amblyopia 569. 1%; AlconCusi, Barcelona, Spain (b) (4)

21 Arnold RW Duration and Effect of Single Dose Atropine: Paralysis of Binocular Vision & 2004 Alcon Accommodation in Penalization Treatment of Strabismus Quarterly; Functional Amblyopia 19(2):81-86. 22 Auffarth G Cycloplegic refraction in children: Single-dose- Documenta Ophthmologica 1992 Not identified atropinization versus three day atropinization 80:353-362 23 Bartlett, JD Administration of and Adverse Reactions to Cycloplegic Am J Optometry 55(4): 227- 1978 Not identified Agents 233

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 11 NDA 208-151

# First Author Title Journal Year Source of Drug Product 24 Bothman L Homatropine and Atropine Cycloplegia: A comparative Arch Ophthalmology 7:389- 1932 Not identified study 398 25 Boudet J Dose-response effects of atropine in human volunteers Fundam Clin Pharmacol. 1991 Not identified 5:635-640 26 Choo The studies on the Residual Accommodation of Koreans Yonsei Medical Journal 1963 Not identified 4:73-76. 27 Cowan EC Clinical Evaluation of a New Mydriatic - Mydrilate Brit J Ophthalmol 46:730- 1962 Not identified 736. 28 Cristini G The Vascular Action of Pilocarpine, Eserine, Adrealine Brit J Ophthalmol 33:228- 1949 Not identified and Atropine and their influence in Primary Chonic 242 Glaucoma 29 Emiru VP Response to mydriatics in the African Brit J Ophthalmol 55:538- 1971 Not identified 543 30 Farhood QK Cycloplegic Refraction in Children with Cyclopentolate J Clin Exp Ophthalmol 2012 Not identified vs Atropine 3(7):239-244 31 Fraser H Oxyphenonium Bromide as a Mydriatic Brit J Ophthalmol 40:751- 1956 Not identified 753 32 Gettes BC Evaluation of Five New Cycloplegic Drugs Arch Ophthalmol 49:24-27 1953 Not identified 33 Gettes BC Three new cycloplegics drugs Arch Ophthalmol 51:467- 1954 Not identified 472. 34 Hartgraves H The Synergistic Action of Atropine and Epinephrine on Arch Ophthalmol. 5(2):212- 1931 Not identified the Intrinsic Muscles of the Eye 218 35 Hiatt RL Comparison of Atropine and Tropicamide in Esotropia Annals Ophthalmol 15 (4): 1983 Not identified 341-343 36 Hiraoka T Influences of Cycloplegia with Topical Atropine on Ophthalmol 120:8-13 2013 Not identified Ocular Higher-Order Aberrations 37 Hoefnagel D Toxic Effects of Atropine and Homatropine Eyedrops in New Eng J Med 264:168-171 1961 Not identified Children 38 Ingram RM Refraction of 1-year-old children after atropine Brit J Ophthalmol 63:343- 1979 Not identified cycloplegia 347 39 Ingram RM Refraction of 1-year-old children after cycloplegia with Brit J Ophthalmol 63:348- 1979 Not identified 1% cyclopentolate: comparison with findings after 352 atropinization 40 Jackson E Cycloplegia for Diagnosis Arch Ophthalmol 11(1):133- 1934 Not identified 140 41 Janes RG The Penetration of C14-Labeled Atropine into the Eye Arch Ophthalmol 62(1):69- 1959 Not identified 74 42 Kawamoto K Cycloplegic Refractions in Japanese Children: A Ophthalmologica 211:57-60 1997 Not identified Comparison of Atropine and Cyclopentolate 43 Khurana AK Status of cyclopentolate as a Cycloplegic in Children: A Acta Ophthalmologica 1988 Not identified comparison with Atropine and Homatropine 66:721-724 44 Lahdes K Systemic absorption of topically applied ocular atropine Clin Pharmacol 44:310-314 1988 Star Pharmaceuticals, Tampere, Finland 45 Lowe RF Angle-Closure, Pupil Dilatation and Pupil Block Brit J Ophthalmol 50:385- 1966 Not identified 389 46 Mann I A new synthetic mydriatics Br J Ophthalmol 1946 Not identified 30(1): 8–11 47 Marron J Cycloplegia and Mydriasis by use of Atropine, Arch Ophthalmol 23:340- 1940 Not identified Scopolamine and Homatropine-Paredrine 350 48 Narvaez J Pupil dilation using a standard cataract surgery regimen J Cataract Refract Surg 2010 Not identified alone or with atropine 1.0% pretreatment 36:563-567 49 North RV A Review of the Uses and Adverse Effects of Topical Ophthalmol Physiol Opt 1987 Not identified Administration of Atropine 7(2):109-114 50 Noske W Cycloplegic refraction using atropine minidrops Strabismus 1(1):17-23 1993 Not identified 51 Obianwu HO The relationship between the Mydriatic Action and the Brit J Ophthalmol 49:264- 1965 Not identified Colour of the Iris 270 52 Pendse GS Refraction in Relation to Age and Sex Arch Ophthalmol 52(3):404- 1954 Not identified 412

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 12 NDA 208-151

# First Author Title Journal Year Source of Drug Product 53 Riddell WJB A Clinical Trial of a Synthetic Mydriatic Brit J Ophthalmol 1946 Not identified 30:1-7 (b) (4)

55 Rosenbaum Cycloplegic Refraction in Esotropic Children Ophthalmol 1981 Not identified AL 88:1031-1034 56 Rosenfield M A Comparison of the effects of Cycloplegics on Ophthalmol Physiol Opt 1986 Not identified Accommodation Ability for Distance Vision and the 6(3):317-320 Apparent Near Point 57 Shah BM Comparing homatropine and atropine in pediatric J AAPOS 2011 Not identified cycloplegics refractions 15:245-250 (b) (4)

59 Smith SA Factors determining the Potency of Mydriatic Drugs in Br J Clin Pharm 3:503-507 1976 Support from Smith Man & Nephew 60 Soares R Determination of Atropine Enantiomers in Ophthalmic J AOAC Int. 2009 Not identified Solutions by Liquid Chromatography using a Chiral AGP 92(6):1663-72. Column 61 Stolovitch C Atropine Cycloplegia: How Many Instillations Does One J Pediatr Ophthalmol 1992 Not identified Need? Strabismus 29:175-176 62 Thorne FH Cycloplegics Arch. of Ophthalmol 1939 Not identified 22:274–287 63 Wolf AV Effects of Atropine Sulfate, Methlatropine Nitrate Arch Ophthalmol. 1946 Not identified (Metropine) and Homatropine Hydrobromide on Adult 36(3):293-301 Human Eyes 64 Zetterstrom C A cross-over study of the cycloplegics effects of a single Acta Ophthalmologica 1985 Not identified topical application of cyclopentolate-phenylephrine and 63:525-529 routine atropinization for 3.5 days

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 13 NDA 208-151

5.2 Review Strategy and Linkage (Bridge) to Proposed Product In addition to the applicant’s references (listed as articles 1-20 in the table above), a literature search was conducted using the terms “Atropine” and “Eye.” Abstracts were screened for adequate and well controlled studies. Published clinical trial results were reviewed. References of articles were reviewed for potential additional articles. Sixty-four articles were reviewed in detail. Representative clinical studies were identified and are listed in section 5.3. These studies include subjects from two months through 92 years in age, multiple races, ethnicities and eye colors. These studies are all relevant to the proposed product because they are studies conducted with atropine solution 1%. The active ingredient is chemically the same as the proposed product and the product is dosed topically to the cornea. The drug product has been demonstrated to penetrate the cornea directly to the site of action (iris and ciliary body). The exact formulation for many of the referenced studies relied on to support the safety or efficacy is unknown, although as noted in the table, some were the product which is the subject of this application and were supplied by Alcon. Because Alcon marketed this product for many years, it is likely that some of the references which do not specify the source of the Atropine were also Alcon’s product. It is also likely that several of the individual products were made by multiple different manufacturers over the span of 150 years and the formulations are not exactly the same.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 14 NDA 208-151

5.3 Discussion of Representative Individual Studies/Clinical Trials Publications were reviewed for 4 indications. Study Indication Design Arms (# of subjects) Barbee 1957 Pupil dilation Non-randomized Atropine 1% Double-blind Plus 9 other agents Cycloplegia Total of 300 patients Chia 2012 Pupil dilation Randomized Atropine 0.5% (161) Double-blind Atropine 0.1% (155) Cycloplegia Atropine 0.01% (84) Ebri 2007 Pupil dilation Randomized Atropine 1% (79) Parallel groups Cyclopentolate 1% +Tropicamide 0.5% (78) Cycloplegia Cyclopentolate 1% (76) Marron Pupil dilation Non-randomized Atropine 1% (107) 1940 Scopolamine 0.5% (21) Cycloplegia Homatropine 5% (25) Wolf 1946 Pupil dilation Non-randomized Atropine 1% 15 eyes (13) Open label Methylatropine 1% 23 eyes(21) Cycloplegia Homatropine 1% 7 eyes (7) Kawamoto Cycloplegia Sequential groups Atropine 0.5% (<6yrs old) or 1% (6 and older) 1997 Cyclopentolate 1% Total of 51 children Stolovitch Cycloplegia Subject their own Atropine 1% (36) 1992 control /comparison to baseline Pediatric Amblyopia Randomized Atropine 1% (95) Eye Disease Parallel groups Patching (98) Group 2008 Blinded assessment (b) (4)

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 15 NDA 208-151

6 Review of Efficacy

6.1 Mydriasis and Cycloplegia

Barbee 1957 Double-blind, placebo controlled

3333333 COPYRIGHT MATERIAL WITHHELD

Reviewer's Comments: The parasympatholytic agents, scopolamine, atropine and homatropine all induced significant mydriasis of essentially equal degrees in all three iris color types.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 16 NDA 208-151

Chia 2012 Randomized, Double-blind, 2 year study; Atropine 0.5% (161 subjects), Atropine 0.1% (155 subjects), Atropine 0.01% (84 subjects)

Accommodation (D) 0.01% 0.1% 0.5% Baseline 16.2 (3.4) 16.7 (3.0) 15.8 (3.4) Year 1 11.7 (4.3) 6.0 (3.4) 3.6 (3.2) Year 2 11.8 (3.2) 6.8 (3.4) 4.0 (2.6)

Mesopic pupil diameter (mm) Baseline 3.9 (0.6) 3.9 (0.6) 4.0 (0.7) Year 1 5.1 (0.9) 6.7 (1.0) 7.5 (1.1) Year 2 5.1 (0.9) 6.7 (1.1) 7.5 (1.2)

Photopic pupil diameter (mm) Baseline 4.7 (0.7) 4.6 (0.7) 4.6 (0.7) Year 1 5.6 (0.8) 7.0 (1.0) 7.7 (1.0) Year 2 5.5 (0.8) 6.9 (1.0) 7.8 (1.1)

Reviewer's Comments: This study demonstrates a dose response in both decreasing accommodation and increasing pupil diameters.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 17 NDA 208-151

Ebri 2007 Randomized, Parallel, Active control. Atropine 1% (79 eyes), Cyclopentolate 1%+Tropicamide 0.5% (78 eyes), Cyclopentolate 1% (76 eyes)

Cyclopentolate 1% Tropicamide 0.5% Cyclopentolate Combined Regimen Atropine 1% Residual accommodation 0.0-0.5 D 41 (54%) 55 (71%) 70 (100%) >0.5-1D 24 (32%) 19 (25%) 0 >1.0-1.5D 8 (11%) 2 (3%) 0 >1.5D 3 ( 4%) 1 (1%) 0

Dilated pupil size < 6 mm 36 (47%) 5 (6%) 0 ≥ 6 mm 40 (53%) 72 (94%) 70 (100%)

Response to light Negative 19 (25%) 51 (66%) 68 (97%) Positive 57 (75%) 26 (34%) 2 (3%)

Reviewer's Comments: The study demonstrates superiority of Atropine 1% over Cyclopentolate in both mydriasis and reduction of accommodation.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 18 NDA 208-151

Narvaez J 2010 Pupil dilation using a standard cataract surgery regimen alone or with atropine 1.0% pretreatment

Prospective, unmasked study, the baseline pupil size in 72 eyes of 54 volunteers (age 21-92) was measured. Pupil size was then measured 30 minutes after instillation of phenylephrine 2.5%, tropicamide 1%, and cyclopentolate 1%. Several days later, the subjects returned for repeat measurements after pretreating the study eye(s) with atropine 1%, 3 times a day the day previously and once on the morning of repeat dilation and measurements. Pupil size was again measured after administration of the standard regimen.

Diameter (mm) Baseline pupil size 4.1 ± 0.7 CI (3.9-4.3) Atropine 6.9 ± 1.2 CI (6.9-7.3) Phenylephrine, tropicamide, and cyclopentolate 7.3 ± 1.2 CI (7.0-7.7)

Reviewer's Comments: Pupil increases with atropine were clinically significant but were less than the triple combination of phenylephrine 2.5%, tropicamide 1%, and cyclopentolate 1%.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 19 NDA 208-151

Marron 1940 Atropine 1% (107 eyes), Scopolamine 0.5% (21 eyes), Homatropine 5% (25 eyes)

Atropine: Duration of Maximum Cycloplegia 8-24 hours (10 drops) Time at Which Patient First Reads 3 days Accommodation Normal 18 days Full Mydriasis 40 minutes Duration of Full Mydriasis 8 hours Time when normal diameter appears 12 days

Scopolamine Duration of Maximum Cycloplegia 40 minutes (10 drops) Time at Which Patient First Reads 3 days Accommodation Normal 8 days Full Mydriasis 20 minutes Duration of Full Mydriasis 8 hours Time when normal diameter appears 8 days

Homatropine Duration of Maximum Cycloplegia 50 minutes Paredrine Time at Which Patient First Reads 6 hours Accommodation Normal 36 hours Full Mydriasis 30 minutes Duration of Full Mydriasis 95 minutes Time when normal diameter appears 48 hours

Reviewer's Comments: Administration of atropine 1% resulted in clinically significant mydriasis within 40 minutes and clinically significant cycloplegia for at least 8 hours.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 20 NDA 208-151

Wolf 1946 Atropine 1% 15 eyes, Methylatropine 1% 23 eyes, Homatropine 1% 7 eyes

Maximum Initial Time to Max Pupillary Residual Pupil Mydriasis Cycloplegia Diameter Accommodation Atropine 3.4 40 min 5 hr 8.3 0.21 Methylatropine 3.3 50 min 5 hr 7.7 0.29 Homatropine 3.4 40 min 25 min 5.9 0.55

Recovery Time Mydriasis Cycloplegia Atropine 6 hours 1 day Methylatropine 6 hours 6 hours Homatropine 6 hours 1 hour

Reviewer's Comments: Clinically significant pupil dilation occurred within 40 minutes and lasted for at least 6 hours. Clinically significant cycloplegia occurred within 5 hours lasting for at least one day.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 21 NDA 208-151

Riddell WJB 1946 A Clinical Trial of a Synthetic Mydriatic

The size of the pupils was estimated by means of the pupillometer fitted to the driving wheel of a Morton ophthalmoscope before the drops were placed in the eyes. In five subjects two drops of E.3 were placed in the right eye and two drops of atropine in the left eye. Readings were taken of the size of the pupils at time intervals up to seven days.

Pupil Size (mm) Hours 0 ¼ ½ 1 2 4 5 6 8 10 15 20 21 E.3 4.2 5 5.9 8.2 7.7 7.5 8 7.5 7.7 5 Atropine 1% 4.2 7 8.2 8.3 7.7 7 9 7 8.3 8

Pupil Size (mm) Days 2 3 4 5 6 7 E.3 4.7 3.8 4 3.7 3.8 4.3 Atropine 1% 7.9 7.3 6.7 5.8 6 5.7

Reviewer's Comments: Clinically significant pupil dilation occurred for a duration of at least 4 days.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 22 NDA 208-151

Kawamoto 1997 Atropine 0.5% (<6yrs old), 1% (6 and older), Cyclopentolate 1% Total of 102 eyes of 51 children. Sequential treatment separated by 2-4 months.

Mean Refraction 50 eyes 52 eyes Children younger Children older than 6 years than 6 years Cyclopentolate +2.89 +1.83 Atropine 1% +2.60 Atropine 0.5% +3.55

Difference 0.66 0.77

Reviewer's Comments: The difference in mean refraction represents a difference in accommodation. For each group, treatment with atropine resulted in greater accommodative loss.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 23 NDA 208-151

Farhood 2012 Cycloplegic Refraction in Children with Cyclopentolate vs Atropine

Objective: To evaluate the safety and efficacy of two cycloplegic regimens in hyperopic children. The responses to cycloplegia in different age groups and presence of strabismus were also compared.

Methods: Atropine eye drops 1% bid x 3 days, later followed by cyclopentolate eye drops 1% was evaluated in fifty children aged 3 to 8 years old. Cycloplegic refractions were assessed.

Results: The total refractions were recorded after cycloplegia with atropine 1% or cyclopentolate 1% eye drops. Atropine refraction (mean+3.89 ± 2.45 D) and cyclopentolate refraction (mean +3.58 ± 2.30 D.

Reviewer's Comments: Atropine provided clinically important cycloplegia.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 24 NDA 208-151

Hiatt RL 1983 Comparison of Atropine and Tropicamide in Esotropia

Forty-one patients with esodeviation (82 eyes) were subjected first to 1% tropicamide and retinoscopy and then to retinoscopy after the use of 0.5% to 1% atropine sulfate in children from 2 months to 5 years. There were 20 male and 21 female patients. There were 11 black and 30 white patients. In all cases, there was a greater plus spherical equivalent found with atropine than with tropicamide, and it varied from +0.25 D to as much as + 1.75 D, the average being +0.80 D for the 82 eyes. In general, the higher the plus refractive error, the larger the difference found between atropine and tropicamide.

Reviewer's Comments: Atropine provided clinically important cycloplegia.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 25 NDA 208-151

Stolovitch 1992 Subject own control /comparison to baseline. Atropine 1% 36 patients, 72 eyes. Ages 4 months to 11 years.

Diopters of Hypermetropia found after Four or Eight Instillations of Atropine

No of Eye Instillations Mean RE 8 +2.93 RE 4 +2.91 LE 8 +3.29 LE 4 +3.28

Reviewer's Comments: This study demonstrates that no additional cycloplegic effect occurs between 4 and 8 doses of atropine.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 26 NDA 208-151

Auffarth G 1992 Cycloplegic refraction in children: Single-dose-atropinization versus three day atropinization

Refractive measurements under atropine cycloplegia were tested in 90 strabismic children aged two to seven years. Refraction was determined by an autorefractor 90 minutes after application of two drops of atropine (0.5% atropine children <2.5 years; 1% atropine children >2.5years) and compared with the results after 3 days of receiving 1 atropine eye drops 3 times daily. In 86.5% the spherical equivalents differ not more than 1.0 diopter (p = 0.05); the correlation was 0.99. Astigmatic corrections were in agreement in 95.5%, the axis of cylinders in 93.0%; the correlations were 0.95 and 0.97. The residual accommodation 90 minutes after 2 drops of atropine was not more than 1 diopter in all children. The additional cycloplegic effect of the three-day-atropinization was only 0.5 diopters.

Reviewer's Comments: This article supports the conclusion that 3 days of atropinization is not usually necessary.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 27 NDA 208-151

6.2 Treatment of Amblyopia

Pediatric Eye Disease Group 2008 Randomized Parallel groups masked assessment Atropine 1% vs Patching

Objective: To compare patching with atropine eye drops in the treatment of moderate amblyopia (visual acuity, 20/40-20/100) in children aged 7 to 12 years.

Methods: Randomized, multicenter clinical trial, 193 children with amblyopia were assigned to receive weekend atropine or patching of the sound eye 2 hours per day.

Main Outcome Measure: Masked assessment of visual acuity in the amblyopic eye using the electronic Early Treatment Diabetic Retinopathy Study testing protocol at 17 weeks.

Results: At 17 weeks, visual acuity had improved from baseline by an average of 7.6 letters in the atropine group and 8.6 letters in the patching group. The mean difference between groups (patching − atropine) adjusted for baseline acuity was 1.2 letters (ends of complementary 1- sided 95% confidence intervals for non-inferiority, −0.7, 3.1 letters). This difference met the pre-specified definition for equivalence (confidence interval ≤5 letters). Visual acuity in the amblyopic eye was 20/25 or better in 15 participants in the atropine group (17%) and 20 in the patching group (24%; difference, 7%; 95% confidence interval, −3% to 17%).

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 28 NDA 208-151

Cumulative distribution of visual acuity scores in the amblyopic eye at the 17-week outcome examination, according to treatment group.

Conclusions: Treatment with atropine or patching led to similar degrees of improvement among 7- to 12-year-olds with moderate amblyopia. About 1 in 5 achieved visual acuity of 20/25 or better in the amblyopic eye.

Reviewer's Comments: This study demonstrates a clinically significant improvement in visual acuity achieved by atropine penalization of the eye with better visual function.

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Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 35 NDA 208-151

Reviewer’s Summary Efficacy Conclusion:

There are multiple adequate and well controlled studies which demonstrate the efficacy of atropine solution 1% in producing clinically significant mydriasis and cycloplegia. These studies, along with the adequate and well controlled study in the treatment of amblyopia, are also sufficient to support the efficacy in the treatment of amblyopia because the effectiveness of the treatment of amblyopia is a result of visual penalization due to cycloplegia. (b) (4)

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 36 NDA 208-151

7 Review of Safety 7.1 Methods

7.1.1 Studies/Clinical Trials Used to Evaluate Safety Studies have been conducted to evaluate the effect of atropine on the eyes for over 160 years. Studies range from evaluations of a few patients to studies of over 1500 patients. For example, RM Ingram reported on refractions of 1648 children aged 11 to 13 months in which atropine 1% was used for cycloplegia.

The published literature includes reviews of the adverse events of topical atropine as well as individual case reports. Mydriasis and cycloplegia studies often used one to three day regiments of administration. Studies of the treatment (b) (4) amblyopia used daily administrations for periods of months (amblyopia)(b) (4)

7.1.2 Categorization of Adverse Events Adverse events related to the use of atropine are directly related to its anticholinergic pharmacologic properties. Atropine is an antimuscarinic. It acts directly on smooth and cardiac muscle and on exocrine glands innervated by postganglionic parasympathetic nerves blocking the action of acetylcholine.

7.2 Adequacy of Safety Assessments

7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations

Due to the long history and frequent use of atropine solution, there has been adequate exposure for safety evaluation.

7.2.2 Explorations for Dose Response Atropine eye drops in concentrations from 0.1% through 1% have been demonstrated to produce clinically significant pupillary dilation and cycloplegia.

7.2.3 Special Animal and/or In Vitro Testing None

7.3 Major Safety Results

7.3.1 Deaths Deaths have occurred rarely in young children with significant contributory medical conditions. Five reported cases of death have occurred, all in children under 3 years of

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 37 NDA 208-151

age in which the patients also had severe congenital problems including a patent ductus arteriosus in two patients.

7.3.2 Nonfatal Serious Adverse Events See section 7.3.4.

7.3.3 Dropouts and/or Discontinuations The majority of reported use involves a single course over a couple of days or a single administration of atropine. In most cases, there was not opportunity to discontinue or dropout once therapy had been administered.

7.3.4 Significant Adverse Events The following are the most commonly reported and clinically significant reported adverse reactions. With the exception of the allergic reactions, all are a result of the known and expected pharmacologic action.

Allergic reactions including contact dermatitis usually confined to the lids and conjunctiva characterized by itching, redness, swelling and discharge.

Photophobia due to the increase in pupil size.

Decreased tearing due to inhibition of the lacrimal gland.

Dryness of the skin, mouth and throat due to decreased secretion from the mucous membranes.

Restlessness, irritability or delirium due to stimulation of the central nervous system. Most are thought to be due to atropine intoxication and often associated with pre-existing mental health issues.

Tachycardia. Low dose atropine will initially cause a slowing of the heart rate, but increased dosing can lead to tachycardia.

Flushed skin of face and neck is an expected pharmacologic anticholinergic reaction.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 38 NDA 208-151

7.4 Supportive Safety Results

7.4.1 Common Adverse Events Light sensitivity is usually the most commonly reported adverse reaction. The most frequently reported systemic events are usually dry mouth, irritability and headaches.

7.4.2 Laboratory Findings Abnormal clinical laboratory data was not reported in the published study reports. Atropine is not known to cause changes in laboratory findings.

7.4.3 Vital Signs Atropine is well known in low doses to slow the heart rate, but continued or larger doses will cause tachycardia.

7.4.4 Electrocardiograms (ECGs) No ECG was reported in the studies performed.

7.4.5 Special Safety Studies/Clinical Trials No special studies were conducted.

7.4.6 Immunogenicity Atropine is not believed to cause immunogenicity.

7.5 Other Safety Explorations

Drug-Drug Interactions The use of atropine and monoamine oxidase inhibitor (MAOI) is generally not recommended because of the potential to precipitate hypertensive crisis.

7.6 Additional Safety Evaluations

7.6.1 Human Carcinogenicity Atropine sulfate has not demonstrated any genotoxic potential and has not been shown to be carcinogenic.

7.6.2 Human Reproduction and Pregnancy Data Animal reproduction studies with topical ophthalmic atropine solution have not been conducted. Systemic inhibition of the cholinergic system can interfere with reproductive systems.

Reference ID: 3985196 Clinical Review Wiley A. Chambers, MD 39 NDA 208-151

7.6.3 Pediatrics and Assessment of Effects on Growth Evidence is suggestive of a reduction in the growth of the eye following chronic use of atropine; however, there is limited information beyond two to three years of use. The effect does appear to be dose dependent.

Due to the high systemic exposure following use, the limited need for cycloplegia in children under 3 months, the limited need for amblyopia treatment by pharmacologic penalization in children under 3 months and the availability of alternative drug products for pupillary dilation, atropine 1% solution is not recommended for use in children under the age of 3 months. Use in children under 30 months of age should be limited to no more than a single drop per day.

7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound The signs and symptoms of atropine poisoning or overdose have been well described and are often described by phrases such as: “hot as a hare, red as a beet, dry as a bone, blind as a bat and mad as a hatter.” Severe cases of intoxication can result in ataxia, insomnia, drowsiness, convulsions, high fever and coma. [North RV, Kelly ME. Uses and adverse effects of Atropine. Ophthalmol Physiol Opt. 1987; 7(2):109-114.]

7.7 Summary of Safety

The safety of atropine ophthalmic solution 1% in children greater than 3 months of age and in adults is supported by adequate and well controlled studies in the literature.

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Reference ID: 3985196 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------WILEY A CHAMBERS 09/13/2016

WILLIAM M BOYD 09/13/2016

Reference ID: 3985196 CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement

NDA Number: 208151 Applicant: Alcon Research Stamp Date: 2/12/2016 Ltd. Drug Name: Atropine 1% NDAType: Original NDA 505(b)(2) (atropine sulfate ophthalmic solution)

On initial overview of the NDA/BLA application for filing:

Content Parameter Yes No NA Comment FORMAT/ORGANIZATION/LEGIBILITY 1. Identify the general format that has been used for this eCTD application, e.g. electronic common technical document (eCTD). 2. Is the clinical section legible and organized in a manner to X allow substantive review to begin? 3. Is the clinical section indexed (using a table of contents) X and paginated in a manner to allow substantive review to begin? 4. For an electronic submission, is it possible to navigate the X application in order to allow a substantive review to begin (e.g., are the bookmarks adequate)? 5. Are all documents submitted in English or are English X translations provided when necessary? LABELING 6. Has the applicant submitted a draft prescribing information X that appears to be consistent with the Physician Labeling Rule (PLR) regulations and guidances (see http://www.fda.gov/Drugs/GuidanceComplianceRegulatory Information/LawsActsandRules/ucm084159.htm SUMMARIES 7. Has the applicant submitted all the required discipline X summaries (i.e., Module 2 summaries)? 8. Has the applicant submitted the integrated summary of X safety (ISS)? 9. Has the applicant submitted the integrated summary of X efficacy (ISE)? 10. Has the applicant submitted a benefit-risk analysis for the X product? 11. Indicate if the Application is a 505(b)(1) or a 505(b)(2). 505(b)(2) 505(b)(2) Applications 12. If appropriate, what is the relied upon listed drug(s)? Literature 13. Did the applicant provide a scientific bridge demonstrating No the relationship between the proposed product and the listed drug(s)/published literature? 14. Describe the scientific bridge (e.g., BA/BE studies) Same active ingredient used in clinical literature DOSAGE 15. If needed, has the applicant made an appropriate attempt to X determine the correct dosage regimen for this product (e.g., appropriately designed dose-ranging studies)? Study Number: Study Title:

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Reference ID: 3911780

CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement

Content Parameter Yes No NA Comment mapping investigator verbatim terms to preferred terms? 26. Has the applicant adequately evaluated the safety issues that X are known to occur with the drugs in the class to which the new drug belongs? 27. Have narrative summaries been submitted for all deaths and X adverse dropouts (and serious adverse events if requested by the Division)? OTHER STUDIES 28. Has the applicant submitted all special studies/data X requested by the Division during pre-submission discussions? 29. For Rx-to-OTC switch and direct-to-OTC applications, are X the necessary consumer behavioral studies included (e.g., label comprehension, self selection and/or actual use)? PEDIATRIC USE 30. Has the applicant submitted the pediatric assessment, or X provided documentation for a waiver and/or deferral? PREGNANCY, LACTATION, AND FEMALES AND MALES OF REPRODUCTIVE POTENTIAL USE 31. For applications with labeling required to be in Pregnancy X and Lactation Labeling Rule (PLLR) format, has the applicant submitted a review of the available information regarding use in pregnant, lactating women, and females and males of reproductive potential (e.g., published literature, pharmacovigilance database, pregnancy registry) in Module 1 (see http://www.fda.gov/Drugs/DevelopmentApprovalProcess/D evelopmentResources/Labeling/ucm093307 htm)? ABUSE LIABILITY 32. If relevant, has the applicant submitted information to X assess the abuse liability of the product? FOREIGN STUDIES 33. Has the applicant submitted a rationale for assuming the X applicability of foreign data in the submission to the U.S. population? DATASETS 34. Has the applicant submitted datasets in a format to allow X reasonable review of the patient data? 35. Has the applicant submitted datasets in the format agreed to X previously by the Division? 36. Are all datasets for pivotal efficacy studies available and X complete for all indications requested? 37. Are all datasets to support the critical safety analyses X available and complete? 38. For the major derived or composite endpoints, are all of the X raw data needed to derive these endpoints included? CASE REPORT FORMS 39. Has the applicant submitted all required Case Report Forms X in a legible format (deaths, serious adverse events, and

as needed; however, if it is submitted as a PDF document, it should be submitted in both directions (verbatim -> preferred and preferred -> verbatim). File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908 3

Reference ID: 3911780 CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement

Content Parameter Yes No NA Comment adverse dropouts)? 40. Has the applicant submitted all additional Case Report X Forms (beyond deaths, serious adverse events, and adverse drop-outs) as previously requested by the Division? FINANCIAL DISCLOSURE 41. Has the applicant submitted the required Financial X Disclosure information? GOOD CLINICAL PRACTICE 42. Is there a statement of Good Clinical Practice; that all X clinical studies were conducted under the supervision of an IRB and with adequate informed consent procedures?

IS THE CLINICAL SECTION OF THE APPLICATION FILEABLE? ___Yes___

If the Application is not fileable from the clinical perspective, state the reasons and provide comments to be sent to the Applicant.

Please identify and list any potential review issues to be forwarded to the Applicant for the 74- day letter.

None.

Wiley A. Chambers, MD April 4, 2016 Reviewing Medical Officer Date

William Boyd, MD April 4, 2016 Clinical Team Leader Date

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Reference ID: 3911780 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------WILEY A CHAMBERS 04/04/2016

WILLIAM M BOYD 04/04/2016

Reference ID: 3911780